The mammalian olfactory system consists of at least two functionally distinct organs, the main olfactory epithelium and the vomeronasal organ (VNO). The VNO, a pair of tubular structures at the rostral end of the nasal cavity, is thought to mediate detection of pheromones, chemical signals that regulate reproductive and social behavior and neuroendocrine status. Sensory transduction in the VNO is distinct from that in the main olfactory epithelium, and remains poorly understood. The experiments proposed in this application will test the hypothesis that sensory transduction in the VNO is mediated by a signaling pathway similar to that which mediates phototransduction in invertebrates. In support of this hypothesis, the PI has recently found a VNO-specific homolog (TRP2) of the Drosophila light-activated channel (dTRP) that is highly localized to sensory microvilli of rat vomeronasal sensory neurons. The proposed research is aimed at elucidating the role of the TRP2 channel in vomeronasal sensory transduction, and in VNO-mediated behaviors. A central goal of this work is to identify second messenger pathways that activate TRP2. Extensive studies in Drosophila suggest that activation of dTRP is downstream of phospholipase C, but the direct stimulus for opening dTRP channels is not known. The PI will use techniques of patch-clamp recording and ratiometric calcium imaging in heterologous cell types to study gating of TRP2 in response to receptor-mediated stimulation of phospholipase C and direct application of putative second messengers. A second goal is to identify molecules that interact with TRP2 in a yeast two-hybrid screen of a VNO-cDNA library. By analogy to Drosophila phototransduction, the PI expects TRP2 to be part of a signaling complex that includes other components of the sensory transduction cascade. It has recently been recognized that air-borne pheromones play a role in regulating human reproduction as seen in the menstrual synchrony of women who are in close contact. The sensory reception of human pheromones is not well understood, but may be mediated by the VNO, a structure previously thought to be vestigial in humans. The proposed experiments to elucidate basic mechanisms of sensory transduction in the VNO may, thus, provide a better understanding of the control of human reproductive function.